Oral Delivery Of Peptides

The oral delivery of moderate-sized peptides for the treatment of chronic diseases has been a long sought after goal of many researchers and companies. However, achieving reasonable oral bioavailabilities for peptides has been a challenge due to acid-catalyzed and enzymatic degradation in the gastrointestinal tract, and more importantly, poor permeation across the intestinal epithelium due to the inherent high molecular weight and hydrogen-binding capability of the peptides.

A recent collaboration between MIT’s Department of Chemical Engineering and Harvard Medical School suggests a new approach to this problem may allow the delivery of a payload of peptides across the intestinal epithelium [Pridgen et al., Sci Transl Med, 5, 213ra167 (2013)]. These authors loaded insulin in nanoparticles made of poly(lactic acid)–poly(ethylene glycol) (PLA-PEG) block copolymers. By attaching the Fc portion of IgG to the outside of the particles via maleimide conjugation, the authors generated 57 nm nanoparticles which target the neonatal Fc receptor (FcRn) in the intestinal epithelium. FcRn is well known for its ability to transport IgG in breast milk from mother to infants. This work intends to leverage the observation that FcRn is expressed in the apical region of intestinal epithelial cells into human adulthood [Israel et al., Immunology, 92, 69-74 (1997)].

The authors utilized 14C-labeled nanoparticles to assess uptake. The Fc-targeted nanoparticles showed an 11.5-fold higher absorption efficiency compared to the non-targeted particles. Mice which were administered the targeted insulin nanoparticles showed a dose-dependent blood glucose lowering. The authors also demonstrated that free insulin, insulin in non-targeted nanoparticles, and targeted insulin nanoparticles given with excess IgG were not effective. Finally, targeted insulin nanoparticles given to FcRn knockout mice were not effective. These data suggest that the use of Fc-targeted nanoparticles may be a particularly useful way to deliver peptides orally.